It is well-known that the juvenile years in both humans and animals are marked by a high capacity for learning and memory. It has been postulated that the decrease in the performance of learning and memory after juvenile years may be a result of genetic changes in a set of molecules important for plasticity such as decrease in the NMDA receptor's NR2B subunit expression in the adult brain. Our previous studies have demonstrated that transgenic overexpression of NR2B subunit in the adult brain leads to enhanced NMDAR current, plasticity, and learning and memory in mice. The long-term goals of this project are to understand the role of age-dependent regulation of gene expression in synaptic plasticity and learning and memory, and to provide a molecular basis for exploring potential strategies for treating learning and memory disorders in patients. This application will test the key hypothesis that the C-terminal domains of the NR2 subunits are part of coincidence-detection function of the NMDA receptor essential for optimal learning and memory. This project is aimed at the genetic dissection and identification of molecular motifs within the NR2 subunits that are crucial for the detection and processing of synaptic coincidence-activity during learning and memory. The first set of experiments will focus on the production of 6 types of genetically modified mice in which the NMDA receptor 2 subunit motifs are systematically manipulated in the mouse forebrain region. The second set of experiments involve a series of integrated analyses at cellular, electrophysiological and behavioral levels that are aimed to identify the structural motif essential for enhancing learning and memory in vivo. The successful identification of such crucial molecular motifs with the NMDA receptor should provide new insights into the cellular mechanism underlying memory function and dysfunction in the brain.